title: TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy.
abstract: OBJECTIVE
  Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogeneous muscular disease that presents with muscular dystrophy, joint contractures, and cardiomyopathy with conduction defects. Mutations in several nuclear envelope protein genes have been associated with EDMD in less than half of patients, implying the existence of other causative and modifier genes. We therefore analyzed TMEM43, which encodes LUMA, a newly identified nuclear membrane protein and also a binding partner of emerin and lamins, to investigate whether LUMA may contribute to the pathomechanism of EDMD-related myopathy.
  
  
  METHODS
  Forty-one patients with EDMD-related myopathy were enrolled. In vitro and in vivo transfection analyses were performed to assay the binding partners and oligomerization of mutant LUMA.
  
  
  RESULTS
  We identified heterozygous missense mutations, p.Glu85Lys and p.Ile91Val in TMEM43, in 2 EDMD-related myopathy patients. Reduced nuclear staining of LUMA was observed in the muscle from the patient with p.Glu85Lys mutation. By in vitro transfection analysis, p.Glu85Lys mutant LUMA resulted to failure in oligomerization, a process that may be important for protein complex formation on nuclear membrane. Furthermore, we demonstrated for the first time that LUMA can interact with another nuclear membrane protein, SUN2, in addition to emerin. Cells expressing mutant LUMA revealed reduced nuclear staining with or without aggregates of emerin and SUN2 together with a higher proportion of abnormally shaped nuclei. In vivo expression of mutant LUMA by electroporation in mouse tibialis anterior muscles likewise demonstrated the decreased staining of emerin and SUN2 on myonuclei.
  
  
  CONCLUSIONS
  Our results suggest that mutant LUMAs may be associated with EDMD-related myopathy.
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Liang
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuhashi
authors.forename: Etsuko
authors.initials: E
authors.lastname: Keduka
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D018274:Electroporation / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000473:pathology*; D016297:Mutagenesis, Site-Directed / Q000379:methods; D020125:Mutation, Missense / Q000235:genetics*; D014162:Transfection / Q000379:methods
chemical_list: C107941:CREB3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C413025:SUN2 protein, human; C528696:TMEM43 protein, human